Project Summary/Abstract Despite advances and treatments in autoimmune disease, there remains an unmet need for safer and more effective therapies that are tailored to the individual patient. These advances cannot occur without significant advances in our knowledge and understanding of disease mechanisms. With support from the Autoimmunity Centers of Excellence, we assembled a consortium of outstanding collaborating sites 5 years ago to form ?The Feinstein Institute for Medical Research Center for Clinical Research in Autoimmune Disease?. The overarching theme of our Center is that tissue injury occurring in autoimmune disease is often the end-result of multiple and often redundant inflammatory pathways and mediators (cytokines). We continue to believe that an anti-inflammatory approach that modulates multiple inflammatory mediators will be associated with greater clinical efficacy and we will seek agents with improved tolerability and a better safety profile than therapeutic options that are currently available. Towards this end, we now propose two clinical trials, one targeting cognitive impairment in SLE and the other in Juvenile Rheumatoid Arthritis. We are proposing to ?repurpose? a safe, widely available angiotensin inhibitor that crosses the blood-brain-barrier for treatment of the cognitive impairment that affects so many patients with SLE. In the laboratory, this medication has been shown to reduce neuronal injury by microglia. We will use sophisticated brain imaging techniques to evaluate the effects in patients with SLE. The second study we propose is to use ?bioelectronic medicine to reduce arthritis in children with JIA (juvenile idiopathic arthritis). We will activate the cholinergic anti-inflammatory pathway by stimulating the vagus nerve with a non-invasive, non- painful mild electric current. In the laboratory, stimulating the vagus nerve reduces the production of inflammatory cytokines. Both studies are designed to evaluate efficacy and safety, and both are accompanied by integrated mechanistic studies to learn more about the biologic effects of the intervention. Each is also designed to identify potential biomarkers of response. This Center will continue to strive to conduct collaborative innovative clinical trials that will 1) promote improved patient outcomes through control of inflammatory disease and a reduction of organ damage and dysfunction, 2) result in a better understanding of the pathogenesis of autoimmune diseases and mechanisms for therapeutic responses, 3) lead to a personalized medicine approach to treatment of autoimmune disease 4) evaluate agents that do not cause clinically significant immunosuppresion and 5) conduct collaborative innovative clinical trials that would not be pursued by the pharmaceutical industry.